EP1003503A1 - Combinaisons therapeutiques comprenant de l'amlodipine et de l'atorvastatine - Google Patents

Combinaisons therapeutiques comprenant de l'amlodipine et de l'atorvastatine

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Publication number
EP1003503A1
EP1003503A1 EP98936587A EP98936587A EP1003503A1 EP 1003503 A1 EP1003503 A1 EP 1003503A1 EP 98936587 A EP98936587 A EP 98936587A EP 98936587 A EP98936587 A EP 98936587A EP 1003503 A1 EP1003503 A1 EP 1003503A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
atorvastatin
daim
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP98936587A
Other languages
German (de)
English (en)
Other versions
EP1003503B1 (fr
Inventor
Jan Buch
Robert Andrew Donald Scott
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
Original Assignee
Pfizer Inc
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22009597&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1003503(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to DK98936587T priority Critical patent/DK1003503T3/da
Priority to DK04013754T priority patent/DK1491193T3/da
Priority to EP04013717A priority patent/EP1468682A1/fr
Priority to EP04013754A priority patent/EP1491193B1/fr
Priority to SI9830696T priority patent/SI1003503T1/xx
Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of EP1003503A1 publication Critical patent/EP1003503A1/fr
Publication of EP1003503B1 publication Critical patent/EP1003503B1/fr
Application granted granted Critical
Priority to CY20061101012T priority patent/CY1105108T1/el
Anticipated expiration legal-status Critical
Revoked legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to pharmaceutical combinations of amlodipine and pharmaceutically acceptable acid addition salts thereof and atorvastatin and pharmaceutically acceptable salts thereof, kits containing such combinations and methods of using such combinations to treat subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and to treat subjects presenting with symptoms of cardiac risk, including humans.
  • This invention also relates to additive and synergistic combinations of amlodipine and atorvastatin whereby those additive and synergistic combinations are useful in treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and those subjects presenting with symptoms or signs of cardiac risk, including humans.
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase.
  • Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
  • Atorvastatin calcium disclosed in U.S. Patent No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitor ® and has the formula
  • Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA.
  • atorvastatin calcium is a potent lipid lowering compound.
  • the free carboxylic acid form of atorvastatin exists predominantly as the lactone of the formula and is disclosed in U.S. Patent No. 4,681,893, which is incorporated herein by reference.
  • Amlodipine and related dihydropyridine compounds are disclosed in U.S. Patent No. 4,572,909, which is incorporated herein by reference, as potent anti- ischemic and antihypertensive agents.
  • U.S. Patent No.4,879,303 which is incorporated herein by reference, discloses amlodipine benzenesulfonate salt (also termed amlodipine besylate).
  • Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers.
  • amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine have utility as antihypertensive agents and as antiischemic agents.
  • Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in U.S. Patent No. 5,155,120 as having utility in the treatment of congestive heart failure.
  • Amlodipine besylate is currently sold as Norvasc ® .
  • Amlodipine has the formula
  • Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries.
  • Atherosclerotic coronary heart disease (hereinafter termed "CHD") accounts for 53% of all deaths attributable to a cardiovascular event.
  • CHD accounts for nearly one-half (about $50-60 billion) of the total U.S. cardiovascular healthcare expenditures and about 6% of the overall national medical bill each year.
  • CHD remains the most common cause of death in the United States.
  • HMG-CoA reductase 3-hydroxy-3-methylglutaryl- coenzyme A reductase
  • LDL-C low density lipoprotein cholesterol
  • Angina pectoris is a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the left arm. Often angina pectoris is due to ischemia of the heart and is usually caused by coronary disease.
  • symptomatic angina pectoris varies significantly from country to country.
  • patients who present with symptomatic, stable angina pectoris are frequently treated with surgical procedures or PTCA.
  • Patients who undergo PTCA or other surgical procedures designed to treat angina pectoris frequently experience complications such as restenosis.
  • This restenosis may be manifested either as a short term proliferative response to angioplasty-induced trauma or as long term progression of the atherosclerotic process in both graft vessels and angioplastied segments.
  • NASH National Cholesterol Education Program
  • Amlodipine helps to prevent myocardial ischemia in patients with exertional angina pectoris by reducing Total Peripheral Resistance, or afterioad, which reduces the rate pressure product and thus myocardial oxygen demand at any particular level of exercise.
  • amlodipine has been demonstrated to block constriction and thus restore myocardial oxygen supply. Further, amlodipine has been shown to increase myocardial oxygen supply by dilating the coronary arteries.
  • Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is potentially due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions.
  • Coronary heart disease is a multifactorial disease in which the incidence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject. Incidence is also affected by smoking and left ventricular hypertrophy which is secondary to hypertension. To meaningfully reduce the risk of coronary heart disease, it is important to manage the entire risk spectrum. For example, hypertension intervention trials have failed to demonstrate full normalization in cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the risk of cardiovascular morbidity and mortality.
  • the Framingham Heart Study an ongoing prospective study of adult men and women, has shown that certain risk factors can be used to predict the development of coronary heart disease, (see Wilson et al., Am. J. Cardiol. 1987, 59(14):91G-94G). These factors include age, gender, total cholesterol level, high density lipoprotein (HDL) level, systolic blood pressure, cigarette smoking, glucose intolerance and cardiac enlargement (left ventricular hypertrophy on electrocardiogram, echocardiogram or enlarged heart on chest X-ray). Calculators and computers can easily be programmed using a multivariate logistic function that allows calculation of the conditional probability of cardiovascular events.
  • HDL high density lipoprotein
  • Modeled incidence rates range from less than 1 % to greater than 80% over an arbitrarily selected six year interval. However, these rates are typically less than 10% and rarely exceed 45% in men and 25% in women.
  • composition A a pharmaceutical composition, hereinafter termed "Composition A”, comprising: a. an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof; b. an amount of atorvastatin or a pharmaceutically acceptable salt thereof; and c. a pharmaceutically acceptable carrier or diluent.
  • composition AA of Composition A comprising amlodipine besylate.
  • composition AB a pharmaceutical composition
  • Composition B a first pharmaceutical composition
  • second pharmaceutical composition for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the sum of the antihypertensive and hypolipidemic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable earner or diluent.
  • composition BA a first pharmaceutical composition, hereinafter termed "Composition BA", of Composition B wherein said second pharmaceutical composition comprises amlodipine besylate.
  • Composition BB a first pharmaceutical termed "Composition BB", of Composition BA comprising the hemicalcium salt of atorvastatin.
  • This invention is also directed to a first pharmaceutical composition, hereinafter termed “Composition C”, for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the sum of the antihypertensive and hypolipidemic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • Composition CA a first pharmaceutical composition
  • composition CB a first pharmaceutical composition, hereinafter termed "Composition CB", of Composition CA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
  • composition D a first pharmaceutical composition
  • Composition D for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the antihypertensive and hypolipidemic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition DA a first pharmaceutical composition
  • Composition D comprising amlodipine besylate
  • Composition DB a first pharmaceutical composition
  • said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
  • composition E a first pharmaceutical composition
  • Composition E for use with a second pharmaceutical composition for achieving a antihypertensive effect and a hypolipidemic effect in a mammal suffering from hypertension and hyperlipidemia, which effects are greater than the antihypertensive and hypolipidemic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition EA a first pharmaceutical composition
  • Composition EA a first pharmaceutical composition
  • Composition E a first pharmaceutical composition
  • Composition EB a first pharmaceutical composition
  • composition P a first pharmaceutical composition
  • Composition P for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the sum of the antiangina effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition FA a first pharmaceutical composition, hereinafter termed "Composition FA", of Composition F comprising amlodipine besylate.
  • This invention is more particularly directed to a first pharmaceutical composition, hereinafter termed “Composition FB”, of Composition FA wherein said second pharmaceutical comps ' rtion comprises the hemicalcium salt of atorvastatin.
  • Composition G a first pharmaceutical composition, hereinafter termed “Composition G”, for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the sum of the antiangina effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition GA a first pharmaceutical composition, hereinafter termed "Composition GA”, of Composition G wherein said second pharmaceutical composition comprises amlodipine besylate.
  • composition GB a first pharmaceutical composition, hereinafter tenmed “Composition GB”, of Composition G comprising the hemicalcium salt of atorvastatin.
  • composition H a first pharmaceutical composition, hereinafter termed "Composition H", for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the antianginal effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, acceptable carrier or diluent.
  • composition HA a first pharmaceutical composition, hereinafter termed "Composition HA”, of Composition H comprising amlodipine besylate.
  • composition HB a first pharmaceutical composition
  • Composition J a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an antianginal effect in a mammal suffering from angina pectoris, which effect is greater than the antianginal effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition JA a first pharmaceutical composition, hereinafter termed "Composition JA", of Composition J wherein said second pharmaceutical composition comprises amlodipine besylate.
  • composition JB a first pharmaceutical composition, hereinafter termed "Composition JB", of Composition JA comprising the hemicalcium salt of atorvastatin.
  • composition K a first pharmaceutical composition, hereinafter termed "Composition K", for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the sum of the antiatherosclerotic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition KA a first pharmaceutical composition
  • Composition K wherein said second pharmaceutical composition comprises amlodipine besylate.
  • Composition KB a first pharmaceutical composition
  • Composition KC a composition, hereinafter termed "Composition KC” of Composition KB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
  • This invention is still more particularly directed to a composition of Composition KC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
  • This invention is also particularly directed to a composition of Composition KB wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
  • This invention is also particularly directed to a composition of Composition KB wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
  • composition KD a composition, hereinafter termed "Composition KD", of Composition KB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
  • composition KD a composition, hereinafter termed "Composition KD”
  • Composition KD wherein said regression of atherosclerotic plaques occurs in coronary arteries.
  • This invention is also particularly directed to a composition of Composition KD wherein said regression of atherosclerotic plaques occurs in carotid arteries.
  • This invention is also particularly directed to a composition of Composition KD wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
  • This invention is also directed to a first pharmaceutical composition, hereinafter termed “Composition L”, for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the sum of the antiatherosclerotic effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said, first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • Composition LA a first pharmaceutical composition
  • composition LB a first pharmaceutical composition, hereinafter termed "Composition LB", of Composition LA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
  • composition LB composition LB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
  • composition LB composition LB
  • Composition LC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
  • This invention is also particularly directed to a composition of Composition LC wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
  • This invention is also particularly directed to a composition of Composition LC wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
  • composition LD a composition, hereinafter termed "Composition LD", of Composition LB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
  • This invention is still more particularly directed to a composition of Composition LD wherein said regression of atherosclerotic plaques occurs in coronary arteries.
  • This invention is also particularly directed to a composition of Composition LD wherein said regression of atherosclerotic plaques occurs in carotid arteries.
  • This invention is also particularly directed to a composition of Composition LD wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
  • composition M a first pharmaceutical composition, hereinafter , termed "Composition M”, for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the antiatherosclerotic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical compos ' ition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition MA a first pharmaceutical composition, hereinafter termed "Composition MA”, of Composition M comprising amlodipine besylate.
  • composition MB a first pharmaceutical composition, hereinafter termed "Composition MB", of Composition MA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
  • composition MC of Composition MB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
  • composition of composition MC of Composition MB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
  • Composition MC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
  • This invention is also particularly directed to a composition of Composition MC wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
  • This invention is also particularly directed to a composition of Composition MC wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
  • composition MD a composition, hereinafter termed "Composition MD", of Composition MB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
  • This invention is still more particularly directed to a composition of Composition MD wherein said regression of atherosclerotic plaques occurs in coronary arteries.
  • This invention is also particularly directed to a composition of Composition MD wherein sai ⁇ l regression of atherosclerotic plaques occurs in carotid arteries.
  • This invention is also particularly directed to a composition of Composition MD wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
  • This invention is also directed to a first pharmaceutical composition, hereinafter termed "Composition N", for use with a second pharmaceutical composition for achieving an antiatherosclerotic effect in a mammal, which effect is greater than the antiatherosclerotic effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition NA a first pharmaceutical composition, hereinafter termed "Composition NA”, of Composition N wherein said second pharmaceutical composition comprises amlodipine besylate.
  • composition NB a first pharmaceutical composition, hereinafter termed "Composition NB", of Composition NA comprising the hemicalcium salt of atorvastatin.
  • composition NC composition NB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
  • composition NC composition NB wherein said antiatherosclerotic effect is manifested by a slowing of the progression of atherosclerotic plaques.
  • composition NC composition NB
  • Composition NC wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
  • This invention is also particularly directed to a composition of Composition NC wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
  • This invention is also particularly directed to a composition of Composition NC wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
  • composition ND a composition, hereinafter termed "Composition ND", of Composition NB wherein said antiatherosclerotic effect is manifested by a regression of atherosclerotic plaques.
  • This invention is still more particularly directed to a composition of Composition ND wherein said regression of atherosclerotic plaques occurs in coronary arteries.
  • This invention is also particularly directed to a composition of Composition ND wherein said regression of atherosclerotic plaques occurs in carotid arteries.
  • This invention is also particularly directed to a composition of Composition ND wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
  • composition P a first pharmaceutical composition, hereinafter termed "Composition P”, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the sum of the cardiac risk management effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • Composition P a first pharmaceutical composition for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the sum of the cardiac risk management effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlo
  • composition PA a first pharmaceutical composition, hereinafter termed "Composition PA”, of Composition P comprising amlodipine besylate.
  • This invention is more particularly directed to a first pharmaceutical composition of Composition PA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
  • This invention is also directed to a first pharmaceutical composition, hereinafter termed "Composition Q”, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the sum of the cardiac risk management effects achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceuticat composition comprising., an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • Composition Q a first pharmaceutical composition, hereinafter termed "Composition QA”, of Composition Q wherein said second pharmaceutical composition comprises amlodipine besylate.
  • This invention is more particularly directed to a first pharmaceutical composition of Composition QA comprising the hemicalcium salt of atorvastatin.
  • composition R a first pharmaceutical composition for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the cardiac risk management effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition RA a first pharmaceutical composition, hereinafter termed "Composition RA”, of Composition R comprising amlodipine besylate.
  • This invention is more particularly directed to a first pharmaceutical composition of Composition RA wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.
  • This invention is also directed to a first pharmaceutical composition, hereinafter termed “Composition S”, for use with a second pharmaceutical composition for managing cardiac risk in a mammal at risk of suffering an adverse cardiac event, which effect is greater than the cardiac risk management effects achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable earner or diluent, said first pharmaceutical composition comprising ,an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • Composition SA a first pharmaceutical composition
  • This invention is more particularly directed to a first pharmaceutical composition of Composition S comprising the hemicalcium salt of atorvastatin.
  • Kit A for achieving a therapeutic effect in a mammal comprising: a. an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form; b. an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. container means for containing said first and second dosage forms.
  • Kit AA of Kit A comprising amlodipine besylate.
  • Kit AB of Kit AA comprising the hemicalcium salt of atorvastatin.
  • Kit AA comprising the hemicalcium salt of atorvastatin.
  • Kit AA comprising the hemicalcium salt of atorvastatin.
  • Kit AA comprising the hemicalcium salt of atorvastatin.
  • Kit AB wherein said therapeutic effect is treatment of hypertension and hyperlipidemia.
  • Kit AD a kit, hereinafter termed "Kit AD", of Kit AB wherein said therapeutic effect is treatment of angina pectoris.
  • Kit AE a kit, hereinafter termed "Kit AE”, of Kit AB wherein said therapeutic effect is management of cardiac risk.
  • Kit AB a kit, hereinafter termed "Kit AP, of Kit AB wherein said therapeutic effect is treatment of atherosclerosis.
  • Kit AG Kit AF wherein said treatment of atherosclerosis slows the progression of atherosclerotic plaques.
  • Kit AH a kit, hereinafter termed "Kit AH", of Kit AG wherein said progression of atherosclerotic plaques is slowed in coronary arteries.
  • Kit AJ a kit, hereinafter termed "Kit AJ”, of Kit AG wherein said progression of atherosclerotic plaques is slowed in carotid arteries.
  • Kit AG a kit, hereinafter termed "Kit AK", of Kit AG wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.
  • Kit AF Kit AF wherein said treatment of atherosclerosis causes the regression of atherosclerotic plaques.
  • This invention is still further directed to a kit of Kit AL wherein said regression of atherosclerotic plaques occurs in coronary arteries.
  • This invention is still further directed to a kit of Kit AL wherein said regression of atherosclerotic plaques occurs in carotid arteries.
  • Kit AL a kit of Kit AL wherein said regression of atherosclerotic plaques occurs in the peripheral arterial system.
  • Method A for treating a mammal in need of therapeutic treatment comprising administering to said mammal
  • Method A comprising amlodipine besylate.
  • Method C of Method B comprising the hemicalcium salt of atorvastatin.
  • Method D a method, hereinafter termed "Metiiod D", of Method A wherein said first compound and said second compound are administered simultaneously.
  • Method E a method, hereinafter termed "Method E”, of Method A wherein said first compound and said second compound are administered sequentially in either order.
  • Method F is also particularly directed to a method, hereinafter termed "Method F", of Method C wherein said first compound and said second compound are administered simultaneously.
  • Method G This invention is further directed to a method, hereinafter termed "Method G", of Method C wherein said first compound and said second compound are administered sequentially in either order.
  • Method A said therapeutic treatment comprises antihypertensive treatment and antihyperiipidemic treatment.
  • This invention is still further directed to a method of Method F wherein said therapeutic treatment comprises antihypertensive treatment and antihyperiipidemic treatment.
  • This invention is still further directed to a method of Method G wherein said therapeutic treatment comprises antihypertensive treatment and antihyperiipidemic treatment.
  • This invention is further directed to a method of Method A wherein said therapeutic treatment comprises antianginal treatment.
  • This invention is further directed to a method of Method F wherein said therapeutic treatment comprises antianginal treatment.
  • This invention is further directed to a method of Method G wherein said therapeutic treatment comprises antianginal treatment.
  • This invention is further directed to a method of Method A wherein said therapeutic treatment comprises cardiac risk management.
  • This invention is further directed to a method of Method F wherein said therapeutic treatment comprises cardiac risk management.
  • This invention is further directed to a method of Method G wherein said therapeutic treatment comprises cardiac risk management.
  • This invention is further directed to a method of Method A wherein said therapeutic treatment comprises antiatherosclerotic treatment.
  • This invention is further directed to a method of Method F wherein said therapeutic treatment comprises antiatherosclerotic treatment.
  • This invention is further directed to a method of Method G wherein said therapeutic treatment comprises antiatherosclerotic treatment.
  • Amlodipine is a racemic compound due to the symmetry at position 4 of the dihydropyridine ring.
  • the R and S enantiomers may be prepared as described by Arrowsmith et al., J. Med. Chem., 1986. 22, 1696.
  • the calcium channel blocking activity of amlodipine is substantially confined to the S(-) isomer and to the racemic mixture containing the R(+) and S(-) forms, (see International Patent Application Number PCT/EP94/02697).
  • the R(+) isomer has little or no calcium channel blocking activity. However, the R(+) isomer is a potent inhibitor of smooth muscle cell migration.
  • the R(+) isomer is useful in the treatment or prevention of atherosclerosis, (see International Patent Application Number PCT/EP95/00847). Based on the above, a skilled person could choose the R(+) isomer, the S(-) isomer or the racemic mixture of the R(+) isomer and the S(-) isomer for use in the combination of this invention.
  • cardiac risk means the likelihood that a subject will suffer a future adverse cardiac event such as, e.g., myocardial infarction, cardiac arrest, cardiac failure, cardiac ischaemia. Cardiac risk is calculated using the Framingham Risk Equation as set forth above. The term “cardiac risk management” means that the risk of future adverse cardiac events is substantially reduced.
  • compositions of this invention comprise amlodipine or a pharmaceutically acceptable add addition salt thereof and/or atorvastatin or a pharmaceutically acceptable salt thereof.
  • Amlodipine may readily be prepared as described in U.S. Patent No.
  • Amlodipine besylate which is currently sold as Norvasc ® , may be prepared as described in U.S. Patent No. 4,879,303, which is incorporated herein by reference. Amlodipine and amlodipine besylate are potent and long lasting calcium channel blockers.
  • salts are intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, besylate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesurfonate (tosylate) salts.
  • Other acid addition salts of amlodipine may be prepared by reacting the free base form of amlodipine with the appropriate acid.
  • the salt is of a monobasic add (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate)
  • the hydrogen form of a dibasic add e.g., the hydrogen sulfate, the sucdnate
  • the dihydrogen form of a tribasic add e.g., the dihydrogen phosphate, the citrate
  • at least one molar equivalent and usually a molar excess of the acid is employed.
  • the free base of amlodipine and the add are usually combined in a co-solvent from which the desired salt predpitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
  • Atorvastatin may readily be prepared as described in U.S. Patent No. 4,681,892, which is incorporated herein by reference.
  • the hemicaldum salt of atorvastatin which is currently sold as Lipitor ® , may readily be prepared as described in U.S. Patent No. 5,273,995, which is incorporated herein by reference.
  • the * expression “pharmaceutically acceptable salts” indudes both pharmaceutically acceptable add addition salts and pharmaceutically acceptable cationic salts.
  • pharmaceutically-acceptable cationic salts is intended to define but is not limited to such salts as the alkali metal salts, (e.g. sodium and potassium), alkaline earth metal salts (e.g.
  • benzathine N.N'-dibenzylethylenediamine
  • choline diethanolamine
  • ethylenediamine meglumine (N-methylglucamine)
  • benethamine N-benzylphenethylamine
  • diethylamine piperazine
  • tromethamine (2-amino-2-hydroxymethyl-1 ,3-propanediol) and procaine.
  • pharmaceutically-acceptable add addition salts is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, sucdnate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
  • atorvastatin may be readily prepared by reacting the free add form of atorvastatin with an appropriate base, usually one equivalent, in a co-solvent.
  • bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, caldum hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine.
  • salts are isolated by concentration to dryness or by addition of a non-solvent
  • salts are preferably prepared by mixing a solution of the add with a solution of a different salt of the cation (e.g., sodium or potassium ethylhexanoate, magnesium oleate) and employing a solvent (e.g., ethyl acetate) from which the desired cationic salt precipitates.
  • a solution of the add e.g., sodium or potassium ethylhexanoate, magnesium oleate
  • a solvent e.g., ethyl acetate
  • the acid addition salts of atorvastatin may be readily prepared by reacting the free base form of atorvastatin with the appropriate acid.
  • the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate)
  • the hydrogen form of a dibasic acid e.g., the hydrogen sulfate, the sucdnate
  • the dihydrogen form of a tribasic acid e.g., the dihydrogen phosphate, the citrate
  • at least one molar equivalent and usually a molar excess of the add is employed.
  • amlodipine, pharmaceutically acceptable acid addition salts thereof, atorvastatin and pharmaceutically acceptable salts thereof may occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention.
  • the pharmaceutical combinations and methods of this invention are all adapted to therapeutic use as agents in the treatment of atherosclerosis, angina pectoris, and a condition characterized by the presence of both hypertension and hyperiipidemia in mammals, particularly humans. Further, since these diseases and conditions are dosely related to the development of cardiac disease and adverse cardiac conditions, these combinations and methods, by virtue of their action as antiatherosclerotics, antianginals, antihypertensives and antihyperlipidemics, are useful in the management of cardiac risk.
  • the utility of the compounds of the present invention as medical agents in the treatment of atherosclerosis in mammals (e.g. humans) is demonstrated by the activity of the compounds of this invention in conventional assays and the clinical protocol described below:
  • This study is an angiographic documentation of coronary artery disease carried out as a double-blind, placebo-controlled trial of a minimum of about 500 subjects and preferably of about 780 to about 1200 subjeds. It is especially preferred to study about 1200 subjeds in this study. Subjeds are admitted into the study after satisfying certain entry criteria set forth below.
  • Subjeds accepted for entry into this trial must satisfy certain criteria. Thus the subjed must be an adult, either male or female, aged 18-80 years of age in whom coronary angiography is clinically indicated. Subjeds will have angiographic presence of a significant focal lesion such as 30% to 50% on subsequent evaluation by quantitative coronary angiography (QCA) in a minimum of one segment (non-PTCA, non-bypassed or non-MI vessel) that is judged not likely to require intervention over the next 3 years. It is required that the segments undergoing analysis have not been interfered with. Since percutaneous transluminal cardiac angioplasty (PTCA) interferes with segments by the insertion of a balloon catheter, non-PTCA segments are required for analysis.
  • PTCA percutaneous transluminal cardiac angioplasty
  • segment to be analyzed have not suffered a thrombotic event, such as a myocardial infard (Ml).
  • Ml myocardial infard
  • Segments that will be analyzed include: left main, proximal, mid and distal left anterior descending, first and second diagonal branch, proximal and distal left circumflex, first or largest space obtuse marginal, proximal, mid and distal right coronary artery.
  • Subjeds will have an ejedion fradion of greater than 30% determined by catheterization or radionuclide ventriculography or ECHO cardiogram at the time of the qualifying angiogram or within the previous three months of the acceptance of the qualifying angiogram provided no intervening event such as a thrombotic event or procedure such as PTCA has occurred.
  • subjeds undergo quantitative coronary angiography as well as B-mode carotid artery ultrasonography and assessment of carotid arterial compliance at designated testing centers. This establishes baselines for each subjed.
  • subjeds are randomized to receive amlodipine besylate (10 mgs) and placebo or atorvastatin caldum (80 mgs) and placebo or amlodipine besylate(10 mgs) and atorvastatin, caldum(80 mgs). All doses set forth in this protocol are per day doses. The amount of amlodipine besylate may be varied as required.
  • a subject will start out taking 10 mg and the amount will be titrated down to as little as 5 mg as determined by the dinical physidan.
  • the amount of atorvastatin caldum will similarly be titrated down from 80 mg if it is determined by the physician to be in the best interests of the subjed.
  • the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of atorvastatin calcium may be used in this invention. Calculation of the dosage amount for these other forms of atorvastatin calcium and amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
  • the subjeds are monitored for a one to three year period, generally three years being preferred.
  • B-mode carotid ultrasound assessment of carotid artery atherosderosis and compliance are performed at regular intervals throughout the study.
  • cortiography is performed at the conducion of the one to three year treatment period.
  • the baseline and post-treatment angiograms and the intervening carotid artery B-mode ultrasonograms are evaluated for new lesions or progression of existing atherosclerotic lesions.
  • Arterial compliance measurements are assessed for changes from baseline and over the 6-month evaluation periods.
  • the primary objedive of this study is to show that the combination of amlodipine or pharmaceutically acceptable add addition salts thereof and atorvastatin or pharmaceutically acceptable salts thereof reduces the progression of atherosderotic lesions as measured by quantitative coronary angiography (QCA) in subjeds with clinical coronary artery disease.
  • QCA measures the opening in the lumen of the arteries measured.
  • the primary endpoint of the study is the change in the average mean segment diameter of the coronary artery tree.
  • the diameter of an arterial segment is measured at various portions along the length of that segment.
  • the average diameter of that segment is then determined.
  • the average of all segment averages is determined to arrive at the average mean segment diameter.
  • the mean segment diameter of subjeds taking atorvastatin or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable add addition salts thereof will decline more slowly, will be halted completely, or there will be an increase in the mean segment diameter.
  • the secondary objedive of this study is to show that the combination of amlodipine or a pharmaceutically acceptable acid addtion salt thereof and atorvastatin or a pharmaceutically salt thereof reduces the rate of progression of atherosclerosis in the carotid arteries as measured by the slope of the maximum intimal-medial thickness measurements averaged over 12 separate wall segments (Mean Max) as a function of time, more than does amlodipine or a pharmaceutically acceptable acid addition salt thereof or atorvastatin or a pharmaceutically acceptable salt thereof alone.
  • the intimal-medial thickness of subjeds taking atorvastatin or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable acid addition salt thereof will increase more slowly, will cease to increase or will decrease.
  • Subjeds are males or females between 18 and 80 years of age with a history of typical chest pain assodated with one of the following objedive evidences of cardiac ischemia: (1 ) stress test segment elevation of about one millimeter or more from the ECG; (2) positive treadmill stress test; (3) new wall motion abnormality on ultrasound; or (4) coronary angiogram with a significant qualifying stenosis. Generally a stenosis of about 30-50% is considered to be significant.
  • Each subjed is evaluated for about ten to thirty-two weeks. At least ten weeks are generally required to complete the study. Sufficient subjeds are used in this screen to ensure that about 200 to 800 subjeds and preferably about 400 subjed are evaluated to complete the study. Subjects are screened for compliance with the entry criteria, set forth below, during a four week run in phase. After the screening criteria are met, subjeds are washed out from their current anti-anginal medication and stabilized on a long ading nitrate such as, for example, nitroglycerin, isosorbide- 5-mononitrate or isosorbide dinitrate.
  • ading nitrate such as, for example, nitroglycerin, isosorbide- 5-mononitrate or isosorbide dinitrate.
  • wash out when used in connedion with this screen, means the withdrawal of current anti-anginal medication so that substantially all of said medication is eliminated from the body of the subjed.
  • a period of eight weeks is preferably allowed for both the wash out period and for the establishment of the subjed on stable doses of said nitrate.
  • Subjeds having one or two attacks of angina per week while on stable doses of long ading nitrate are generally permitted to skip the wash out phase. After subjeds are stabilized on nitrates, the subjeds enter the randomization phase provided the subjeds continue to have either one or two angina attacks per week.
  • the subjeds are randomly placed into one of the four arms of the study set forth below.
  • subjeds in compliance with the entry criteria undergo twenty four hour ambulatory eledrocardigram (ECG) such as Holter monitoring, exerdse stress testing such as a treadmill and evaluation of myocardial perfusion using PET (photon emission tomography) scanning to establish a baseline for each subjed.
  • ECG ambulatory eledrocardigram
  • the speed of the treadmill and the gradient of the treadmill can be controlled by a technidan.
  • the speed of the treadmill and the angle of the gradient are generally increased during the test.
  • the time intervals between each speed and gradient increase is generally determined using a modified Bruce Protocol.
  • subjeds are initiated on one of the following four arms of the study: (1) placebo; (2) atorvastatin caldum (about 2.5 mg to about 160 mg); (3) amlodipine besylate(about 2.5 mg to about 20 mg); or (4) a combination of the above doses of amlodipine besylate and atorvastatin caldum together.
  • the subjeds are then monitored for two to twenty four weeks. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of atorvastatin calcium may be used in this invention.
  • Calculation of the dosage amount for these other forms of atorvastatin calcium and amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. After the monitoring period has ended, subjeds will undergo the following investigations: (1) twenty four hour ambulatory ECG, such as Holter monitoring; (2) exercise stress testing (e.g. treadmill using said modified Bruce Protocol); and (3) evaluation of myocardial perfusion using PET scanning. Patients keep a diary of painful ischemic events and nitroglycerine consumption. It is generally desirable to have an accurate record of the number of anginal attacks suffered by the patient during the duration of the test. Since a patient generally takes nitroglycerin to ease the pain of an anginal attack, the number of times that the patient administers nitroglycerine provides a reasonably accurate record of the number of anginal attacks.
  • the person conduding the test will evaluate the subjed using the tests described. Successful treatment will yield fewer instances of ischemic events as deteded by ECG, will allow the subjed to exercise longer or at a higher intensity level on the treadmill, or to exerdse without pain on the treadmill, or will yield better perfusion or fewer perfusion defeds on photoemission tomography (PET).
  • PET photoemission tomography
  • This study is a double blind, parallel arm, randomized study to show the effediveness of amlodipine or pharmaceutically acceptable acid addition salts thereof and atorvastatin or pharmaceutically acceptable salts thereof given in combination in controlling both hypertension and hyperlipidemia in subjeds who have mild, moderate, or severe hypertension and hyperlipidemia.
  • Each subjed is evaluated for 10 to 20 weeks and preferably for 14 weeks. Sufficient subjeds are used in this screen to ensure that about 400 to 800 subjeds are evaluated to complete the study.
  • Subjeds are male or female adults between 18 and 80 years of age having both hyperiipidemia and hypertension. The presence of hyperiipidemia is evidenced by evaluation of the low density lipoprotein (LDL) level of the subjed relative to certain positive risk fadors. If the subjed has no coronary heart disease (CHD) and has less than two positive risk fadors, then the subjed is considered to have hyperiipidemia if the LDL of the subjed is greater than or equal to 190. If the subjed has no CHD and has two or more positive risk fadors, then the subjed is considered to have hyperiipidemia if the LDL of the subjed is greater than or equal to 160. If the subjed has CHD, then the subjed is considered to have hyperlipidemia if the LDL of the subjed is greater than or equal to 130.
  • LDL low density lipoprotein
  • Positive risk fadors include (1) male over 45, (2) female over 55 wherein said female is not undergoing hormone replacement therapy (HRT), (3) family history of premature cardiovascular disease, (4) the subject is a current smoker, (5) the subjed has diabetes, (6) an HDL of less than 45, and (7) the subjed has hypertension.
  • An HDL of greater than 60 is considered a negative risk fador and will offset one of the above mentioned positive risk fadors.
  • BP diastolic blood pressure
  • All blood pressures are generally determined as the average of three measurements taken five minutes apart.
  • Subjeds are screened for compliance with the entry criteria set forth above. After all screening criteria are met, subjeds are washed out from their current antihypertensive and lipid lowering medication and are placed on the NCEP ATP II Step 1 diet.
  • the NCEP ATP II (adult treatment panel, 2nd revision) Step 1 diet sets forth the amount of saturated and unsaturated fat which can be consumed as a proportion of the total caloric intake.
  • the term "washed out" where used in connedion with this screen, means the withdrawal of current antihypertensive and lipid lowering medication so that substantially all of said medication is eliminated from the body of the subjed. Newly diagnosed subjeds generally remain untreated until the test begins.
  • subjeds are also placed on the NCEP Step 1 diet. After the four week wash out and diet stabilization period, subjeds undergo the following baseline investigations: (1) blood pressure and (2) fasting lipid screen.
  • the fasting lipid screen determines baseline lipid levels in the fasting state of a subjed. Generally, the subjed abstains from food for twelve hours, at which time lipid levels are measured.
  • a fixed dose of amlodipine besylate generally about 2.5 to 10 mg
  • a fixed dose of atorvastatin caldum generally about 10 to 80mg
  • a combination of the above doses of amlodipine besylate and atorvastatin caldum together.
  • Subjeds remain on these doses for a minimum of six weeks, and generally for no more than eight weeks. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of atorvastatin caldum may be used in this invention.
  • Calculation of the dosage amount for these other forms of atorvastatin calcium and amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
  • the subjeds return to the testing center at the conclusion of the six to eight weeks so that the baseline evaluations can be repeated.
  • the blood pressure of the subjed at the conducion of the study is compared with the blood pressure of the subjed upon entry.
  • the lipid screen measures the total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoB, VLDL (very low density lipoprotein) and other components of the lipid profile of the subjed. Improvements in the values obtained after treatment relative to pretreatment values indicate the utility of the drug combination.
  • This risk is calculated by using the Framingham Risk Equation.
  • a subjed is considered to be at risk of having a future cardiovascular event if that subjed is more than one standard deviation above the mean as calculated by the Framingham Risk Equation.
  • the study is used to evaluate the efficacy of a fixed combination of amlodipine and atorvastatin in controlling cardiovascular risk by controlling both hypertension and hyperiipidemia in patients who have both mild to moderate hypertension and hyperlipidemia. Each subjed is evaluated for 10 to 20 weeks and preferably for 14 weeks.
  • Suffident subjeds are recruited to ensure that about 400 to 800 subjeds are evaluated to complete the study.
  • Subjeds induded in the study are male or female adult subjeds between 18 and 80 years of age with a baseline five year risk which risk is above the median for said subjed's age and sex, as defined by the Framingham Heart Study, which is an ongoing prospedive study of adult men and women showing that certain risk fadors can be used to predid the development of coronary heart disease.
  • the age, sex, systolic and diastolic blood pressure, smoking habit, presence or absence of carbohydrate intolerance, presence or absence of left ventricular hypertrophy, serum cholesterol and high density lipoprotein (HDL) of more than one standard deviation above the norm for the Framingham Population are all evaluated in determining whether a patient is at risk for adverse cardiac event.
  • the values for the risk fadors are inserted into the Framingham Risk equation and calculated to determine whether a subjed is at risk for a future cardiovascular event. Subj ⁇ ds are screened for compliance with the entry criteria set forth above.
  • the above assays demonstrating the effediveness of amodipine or pharmaceutically acceptable add addition salts thereof and atorvastatin or pharmaceutically acceptable salts thereof in the treatment of angina pedoris, atherosderosis, hypertension and hyperiipidemia together, and the management of cardiac risk also provide a means whereby the adivities of the compounds of this invention can be compared between themselves and with the adivities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
  • dosage amounts and other dosage amounts set forth elsewhere in the specification and in the appendant daims are for an average human subjed having a weight of about 65 kg to about 70 kg.
  • the skilled praditioner will readily be able to determine the dosage amount required for a subjed whose weight falls outside the 65 kg to 70 kg range, based upon the medical history of the subjed and the presence of diseases, e.g., diabetes, in the subjed. All doses set forth herein, and in the appendant daims, are daily doses.
  • amlodipine besylate is generally administered in a dosage of about 2.5 mg to about 20 mg.
  • amlodipine besylate is administered in a dosage of about 5 mg to about 10 mg.
  • the free base form or other salt forms of amlodipine besylate may be used in this invention. Calculation of the dosage amount for these other forms of or the free base form or other salt forms of amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the spedes involved.
  • atorvastatin is administered in a dosage of about 2.5 mg to about 160 mg.
  • atorvastatin is administered in a dosage of about 10 mg to about 80 mg.
  • the free base form or other salt forms of atorvastatin calcium may be used in this invention. Calculation of the dosage amount for these other forms of or the free base form or other salt forms of atorvastatin calcium is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved.
  • the compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable earner or diluent.
  • the compounds of this invention can be administered either individually or together in any conventional oral, parenteral or transdermal dosage form.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various exdpients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are pften very useful for tabletting purposes.
  • Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include ladose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include ladose or milk sugar as well as high molecular weight polyethylene glycols.
  • the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • the combination of this invention may also be administered in a controlled release formulation such as a slow release or a fast release formulation.
  • Such controlled release dosage formulations of the combination of this invention may be prepared using methods well known to those skilled in the art.
  • the method of preferred administration will be determined by the attendant physician or other person skilled in the art after an evaluation of the subject's condition and requirements.
  • the generally preferred formulation of amlodipine is Norvasc ® .
  • the generally preferred formulation of atorvastatin is Lipitor ® .
  • solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • compositions according to the invention may contain 0.1%-
  • the composition or formulation to be administered will contain a quantity of a compound(s) according to the invention in an amount effedive to treat the condition or disease of the subjed being treated. Since the present invention relates to the treatment of diseases and conditions with a combination of adive ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form.
  • the kit includes two separate pharmaceutical compositions: amlodipine or a pharmaceutically acceptable acid addition salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof.
  • the kit includes container means for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container.
  • the kit includes diredions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physidan. It should be understood that the invention is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined by the following claims.

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Abstract

Cette invention se rapporte à des combinaisons pharmaceutiques d'amlodipine ou d'un sel d'addition d'acide de celle-ci, acceptable sur le plan pharmaceutique, et d'atorvastatine ou d'un sel de celle-ci acceptable sur le plan pharmaceutique, à des kits contenant ces combinaisons et à des procédés d'utilisation de ces combinaisons pour traiter des sujets souffrant d'angine de poitrine, d'athérosclérose, d'hypertension et d'hyperlipidémie combinées et pour traiter des sujets présentant des symptômes de risques cardiaques, y compris chez l'homme. Cette invention se rapporte également à des combinaisons additives et synergiques d'amlodipine et d'atorvastatine, qui servent à traiter des sujets souffrants d'angine de poitrine, d'athérosclérose, d'hypertension et d'hyperlipidémie combinées et des sujets présentant des symptômes de risques cardiaques, y compris chez l'homme.
EP98936587A 1997-08-29 1998-08-11 Combinaisons therapeutiques comprenant de l'amlodipine et de l'atorvastatine Revoked EP1003503B1 (fr)

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DK04013754T DK1491193T3 (da) 1997-08-29 1998-08-11 Terapeutiske kombinationer omfattende amlodipin og atorvastatin
EP04013717A EP1468682A1 (fr) 1997-08-29 1998-08-11 Compositions thérapeutiques contenant de l'amlodipine et de l'atorvastatine
EP04013754A EP1491193B1 (fr) 1997-08-29 1998-08-11 Combinaisons thérapeutiques contenant de l'amlodipine et de l'atorvastatine
SI9830696T SI1003503T1 (en) 1997-08-29 1998-08-11 Therapeutic combinations comprising amlodipin and atorvastatin
DK98936587T DK1003503T3 (da) 1997-08-29 1998-08-11 Terapeutiske kombinationer der omfatter amlodipin og atorvastatin
CY20061101012T CY1105108T1 (el) 1997-08-29 2006-07-21 Θepαπευτικοι συνδυασμοι που πepιλαμβανουν αμλοδιπινη και ατορβαστατινη

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US5727597P 1997-08-29 1997-08-29
US57275P 1997-08-29
PCT/IB1998/001225 WO1999011259A1 (fr) 1997-08-29 1998-08-11 Combinaisons therapeutiques comprenant de l'amlodipine et de l'atorvastatine

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EP04013717A Division EP1468682A1 (fr) 1997-08-29 1998-08-11 Compositions thérapeutiques contenant de l'amlodipine et de l'atorvastatine

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EP04013754A Expired - Lifetime EP1491193B1 (fr) 1997-08-29 1998-08-11 Combinaisons thérapeutiques contenant de l'amlodipine et de l'atorvastatine
EP98936587A Revoked EP1003503B1 (fr) 1997-08-29 1998-08-11 Combinaisons therapeutiques comprenant de l'amlodipine et de l'atorvastatine

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DE69835245T2 (de) 2007-07-19
GEP20084338B (fr) 2008-03-25
US20030008904A1 (en) 2003-01-09
EP1491193A1 (fr) 2004-12-29
RS50485B (sr) 2010-03-02
NO320267B1 (no) 2005-11-14
SI1003503T1 (en) 2004-12-31
BG104177A (en) 2000-12-29
JP2010111693A (ja) 2010-05-20
CO4970694A1 (es) 2000-11-07
US20130131125A1 (en) 2013-05-23
PL339092A1 (en) 2000-12-04
JP2001514222A (ja) 2001-09-11
DK1491193T3 (da) 2006-10-16
CA2301732C (fr) 2005-03-29
EP1491193B1 (fr) 2006-07-12
EA003549B1 (ru) 2003-06-26
HUP0003656A3 (en) 2002-10-28
CA2301732A1 (fr) 1999-03-11
BR9812030A (pt) 2000-09-26
WO1999011259A1 (fr) 1999-03-11
US20110201654A1 (en) 2011-08-18
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